Bacterial infections are responsible for an estimated 100,000 deaths in the United States each year, and despite the dire unmet medical need, few new treatment options are being developed. One of the most significant hurdles in effectively treating bacterial infections is the propensity of bacteria to form biofilms. The biofilm serves to protect the bacteria from the host immune system response, and bacteria in the biofilm state are approximately 1000 times more resistant to antibiotics than planktonic (free-floating) bacteria. Identification of small molecules that can effectively prevent the formation of biofilms, or disperse pre-formed biofilms and render bacteria susceptible to antibiotics and to the host immune response, would represent a major advancement in the treatment of bacterial infections. As a postdoctoral scholar in Dr. Christian Melander's Laboratory at NC State University, Dr. Samuel Reyes has synthesized sulfonamide, urea, and thiourea derivatives of marine sponge-derived natural products. These new compounds represent the most potent small molecule inhibitors of P. aeruginosa biofilms discovered to date. P. aeruginosa is a particularly important pathogen that has been implicated in nosocomial and community acquired infections and in chronic pulmonary infections associated with cystic fibrosis. Dr. Reyes' discovery of a new class of non-toxic, synthetically accessible small molecule inhibitors of P. aeruginosa biofilms has the potential to result in the development of a new class of therapeutics for the treatment of P. aeruginosa and other bacterial infections. In this Phase I project, Dr. Reyes will apply a rational approach to synthesize analogues with enhanced activity profiles toward P. aeruginosa and other pathogenic bacterial biofilms. New analogues will be subjected to high throughput screening assays to identify those with activity toward inhibiting and dispersing bacterial biofilms. Lead molecules will be tested against clinical isolates; their synergistic activity with antibiotics will be assessed;and they will be subjected to preliminary toxicity screens. Analogues that show activity toward clinical isolates and demonstrate suitable safety profiles will be considered pre-clinical candidates, and will be further subjected to IND enabling studies in a Phase II program. Successful completion of this project will be facilitated by Dr. Reyes'extensive background in synthetic organic chemistry combined with the microbiology, biochemistry, and drug development expertise of the Agile Sciences'scientists. PUBLIC HEALTH RELEVANCE: Bacterial infections are often difficult to treat due to the propensity of bacteria to form protective biofilms. This project involves the development of a new class of non-toxic small molecules that disrupt bacterial biofilms, rendering the bacteria more sensitive to conventional antibiotics.